Dr Barbara Franke
In the opening session of MoM VIII, Dr Barbara Franke (Radboud University Medical Center, Nijmegen, the Netherlands) highlighted the multifactorial nature, polygenicity and heterogeneity of ADHD.1
Ongoing research into the genetic basis of ADHD
Dr Franke referred to two initiatives that may provide the large sample sizes needed to research specific genes associated with ADHD:
- The Psychiatric Genomics Consortium (PGC) is an international collaboration to conduct a mega-analysis of genome-wide genetic data for psychiatric disorders2
- The International Multi-centre persistent ADHD CollaboraTion (IMpACT) is a consortium of clinical and basic researchers from Europe, the USA and Brazil.3
Dr Franke described a recent IMpACT analysis of whole-exome sequencing across 123 cases of adult ADHD and 82 controls, which has shown significant enrichment of rare genetic variants in a set of 51 previously defined candidate genes for ADHD.4
Potential implications for clinical practice
Drawing on experience from other psychiatric fields, Dr Franke suggested that research into rare and common genetic variants associated with ADHD may improve understanding of the underlying genetic profile of some patients, and that this could potentially be useful from a diagnostic perspective.
- Compared with children of fathers aged 20–24 years, a study has found that children of older fathers (aged 45 years and older) have a heightened risk of autism and ADHD; this is consistent with the hypothesis that new genetic mutations occurring during spermatogenesis are causally related to morbidity in children5
- PGC research has identified 128 common genetic variants that can predict a heightened risk of schizophrenia.6
Dr Franke also described bioinformatic approaches, which have suggested possible associations between the genetic variants implicated in ADHD and:
- Neurite outgrowth (the process of forming neuronal connections during brain development)7
- Ion-gated and ligand-gated channel activity.8,9
Such biological processes could potentially be targeted by treatment.
Finally, Dr Franke noted ongoing research to determine whether the individual genetic/epigenetic profiles of patients with ADHD could be used to select effective non-pharmacological therapy and pharmacological treatments.10 She highlighted so-called ‘therapy-genetics/epigenetics’ and ‘pharmaco-genetics/epigenetics’ as important emerging fields of research.
Dr Franke: “In the next five years, I think common genetic variants, in the form of risk scores, will be able to support diagnosis and we will get insights from bioinformatics for improving treatment. But we need to take a very integrative approach, to integrate findings from different levels of research – cognition neuroimaging and genetics – to support the diagnosis… This will not replace the diagnostic interviews of clinicians, but it will help to reduce the stigma that patients receive because we do not have any biological tests to support the diagnosis.”
- Franke B, Faraone SV, Asherson P, et al. The genetics of attention deficit/hyperactivity disorder in adults, a review. Mol Psychiatry 2012; 17: 960-987.
- Psychiatric Genetics Consortium. What is the PGC? Available at: http://www.med.unc.edu/pgc. Last accessed 13 January 2017.
- IMpACT. Home page. Available at: http://impactadhdgenomics.com. Last accessed 13 January 2017.
- Demontis D, Lescai F, Børglum A, et al. Whole-exome sequencing reveals increased burden of rare functional and disruptive variants in candidate risk genes in individuals with persistent attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 2016; 55: 521-523.
- D’Onofrio BM, Rickert ME, Frans E, et al. Paternal age at childbearing and offspring psychiatric and academic morbidity. JAMA Psychiatry 2014; 71: 432-438.
- Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 2014; 511: 421-427.
- Poelmans G, Pauls DL, Buitelaar JK, et al. Integrated genome-wide association study findings: identification of a neurodevelopmental network for attention deficit hyperactivity disorder. Am J Psychiatry 2011; 168: 365-377.
- Mooney MA, McWeeney SK, Faraone SV, et al. Pathway analysis in attention deficit hyperactivity disorder: An ensemble approach. Am J Med Genet Part B 2016; 17: 815-826.
- Thapar A, Martin J, Mick E, et al. Psychiatric gene discoveries shape evidence on ADHD’s biology. Mol Psychiatry 2016; 21: 1202-1207.
- Bruxel EM, Akutagava-Martins GC, Salatino-Oliveira A, et al. ADHD pharmacogenetics across the life cycle: New findings and perspectives. Am J Med Genet B Neuropsychiatr Genet 2014; 165B: 263-282.